Cellular senescence and its impact on organismal ageing

Our project investigates the impact of senotherapeutic drugs, which target senescent cells – cells, that have stopped dividing but have not died – and their potential to extend health- and lifespan.

Cellular senescence is where cells stop dividing but don't die. Cellular senescence can be caused by external or internal stressors, or that cells have finished dividing. While these cells remain in our tissues and protect us from cancer, they also release molecules that can harm tissues and cells.

A landmark experiment showed that removing senescent cells can boost both life- and health-span, opening up new medical possibilities.

Understanding cellular senescence and its negative impact on our health span is essential for helping individuals, communities and societies live healthier for longer.

This research not only improves quality of life but also has significant implications for global health and wellbeing services.

Cellular senescence is not easy to study since it means working with cells at the end of their life span but a deep understanding of this phase is critical given that it is so harmful for our tissues, bodies and lives.

Scientists have found several pharmaceutical chemicals that can destroy, reverse, or prevent senescent cells. These drugs, some of which are in clinical trials, could be game-changers for human health and longevity.

But first, we need to understand how they work and how they positively, and even negatively, impact cells, tissues and whole organisms.

Studying the effects of senescence-targeting chemicals

There are many aspects to this project, including growing and analysing senescent cells of different differentiation types.

We use several biomarkers to identify senescent cells including radial chromosome positioning which indicates a cell that is senescent due to having divided as much as it can rather than becoming senescent due to stress or reversibly arrested.

We also use gene expression, morphology, the ability to move chromosomes and other pertinent markers to identify senescent cells.

We then test different chemicals to attempt to either kill senescent cells, reverse senescence, or prevent it. These experiments have been successful in the premature ageing disease Hutchinson-Gilford Progeria Syndrome and specific female cancers.

At Brunel University London, we've been using the ramshorn snail as a model organism since 2005.

Our group has found that this snail, when aged, mimics the lack of chromosome movement after a stimulus as human senescent cells do. This makes it a great model organism for studying drug treatments to reverse senescence in a whole organism since we have been studying its chromosomes for a long time.

There are many drugs claiming to extend health and life-span by interfering with cellular senescent pathways and we are studying the safety of these and their effects on cells, both positive and negative.

The public awareness of these drugs and the new wave of medicine that could extend the health span is still limited.

Our project will aim to research why this is and help inform the public, future health professionals and academia about the impact of these drugs.

The Bridger Lab

Professor Bridger has been working to understand senescent cells since her PhD in the early 1990s. She has made significant discoveries in how chromosomes are organised and move inside senescent cells.

Professor Bridger also works with primary cells, which become senescent after many divisions. This is called replicative senescence and is the most prevalent type of cellular senescence in our tissues and bodies.

The Bridger lab has been working with drugs that restore more normal chromosome behaviour in cancer cells and in cells from patients with premature ageing syndromes. We are well-positioned to study the effects of the newly reported seno-therapeutic drugs on cells and even whole organisms, such as the ramshorn snail.

Publications

1. Interphase Chromosomes in Replicative Senescence: Chromosome Positioning as a Senescence Biomarker and the Lack of Nuclear Motor-Driven Chromosome Repositioning in Senescent Cells
   Mehta IS, ..., Bridger JM. Front Cell Dev Biol.2021; 9:640200.
2. Senescence and the Genome
   Bridger JM, Foster HA. 2020. Human Interphase Chromosomes: Biomedical Aspects, 87-106.
3. Genes Responsive to Rapamycin and Serum Deprivation are Clustered on Chromosomes and Undergo Reorganization within Local Chromatin Environments
   Belak ZR, et al. Biochem Cell Biol.2020; 98:178-190.
4. Presence and Distribution of Progerin in HGPS Cells is Ameliorated by Drugs that Impact on the Mevalonate and mTOR Pathways
   Clements CS, ..., Bridger JM. 2019; 20:337-358.
5. Farnesyltransferase Inhibitor and Rapamycin Correct Aberrant Genome Organisation and Decrease DNA Damage Respectively, in HGPS Fibroblasts
   Bikkul MU, ..., Bridger JM. 2018; 19:579-602.
6. The Non-Random Repositioning of Whole Chromosomes and Individual Gene Loci in Interphase Nuclei and its Relevance in Disease, Infection, Aging, and Cancer
   Bridger JM, et al. Adv Exp Med Biol.2014; 773:263-279.
7. Alterations to Nuclear Architecture and Genome Behavior in Senescent Cells
   Mehta IS, ..., Bridger JM. Ann N Y Acad Sci.2007; 1100:250-263.
8. Re-Modelling of Nuclear Architecture in Quiescent and Senescent Human Fibroblasts
   Bridger JM, et al. Curr Biol.2000; 10:149-152.

Meet the Principal Investigator(s) for the project

Dr Joanna Bridger - Our research concerns how the genome is spatially organised, influenced and manipulated within its environment, the cell nucleus. The group has had a number of major advances and is currently focused on aspects of genome behaviour in replicative senescence, the premature ageing disease Hutchinson-Gilford Progeria Syndrome, host:pathogen interactions and female cancers. We are wish to understand how structures such as the nuclear lamina, nucleoskeleton and nuclear motors influence the functionality of the genome in health and disease. Our newest interest is in how the genome can be organised and regulated in low gravity situations and space. 

Related Research Group(s)

Genome Engineering and Maintenance - Diverse research network focused on molecular, cellular, organismal and computational aspects of genome biology.

Project last modified 18/11/2024